The present invention relates to amine hydrofluorides and mixtures of these amine hydrofluorides, and to a process for the preparation of these amine hydrofluorides and their use in oral hygiene compositions.
It is known that oral hygiene compositions, by their cleaning action, make a contribution to the hygiene of the oral cavity and thus to the preservation of the health of teeth and gums. The cleaning action of these oral hygiene compositions is customarily supplemented by admixture of active compounds which prevent or control pathological symptoms in the oral cavity, in particular also the formation of bacterial films on the teeth (plaque). These films consist of polysaccharides, primarily of dextrans. In addition to the low-molecular weight sugars, these polysaccharides form a source of nutrition for the plaque bacteria (mainly streptococci and lactobacillaceae). The plaque bacteria gradually break down the polysaccharides to form acidic degradation products (e.g. pyruvic acid, lactic acid etc.). The pH decrease resulting therefrom brings about the degradation of the tooth enamel known as caries.
It has therefore already been attempted to take steps against the formation of pathological symptoms in the oral cavity using various oral hygiene compositions comprising antibacterially active substances (e.g. toothpastes, rinsing solutions or dental gels). Active compounds already known from the prior art are N-octadeca-9-enylamine hydrofluoride (international non-proprietary name xe2x80x9cdectaflurxe2x80x9d) and in particular Nxe2x80x2-octadecyl-Nxe2x80x2,N,N-tris(2-hydroxyethyl)-1,3-propanediamine dihydrofluoride (international non-proprietary name xe2x80x9colaflurxe2x80x9d). On oral use of the hygiene composition, these active compounds form a thin hydrophobic film on the tooth enamel, the amine hydrofluoride groups coming into contact with the tooth enamel. Thus on the one hand the tooth enamel becomes more resistant to acid attacks on account of the CaF2 covering layer formed, on the other hand the long-chain hydrocarbon residues form a hydrophobic layer which prevents the formation of deposits and the attack of the acidic degradation products on the tooth enamel.
The synthesis of olaflur starts from bovine tallow, a fat having a high stearic acid content. The ester groups are hydrolysed, the free fatty acids are converted into the corresponding amides using ammonia and these are dehydrated to the nitrites. Catalytic reduction thereof yields a mixture of primary fatty amines with the main constituent octadecylamine. Reaction with acrylonitrile and catalytic re-reduction affords N-octadecyl-1,3-propanediamine, which is hydroxyethylated using ethylene oxide. Amounts of by-products are formed here, as the amino groups are in some cases under- or over-substituted. The hydroxyethyl groups introduced can also be etherified by means of further ethylene oxide. The subsequent double hydrofluoridation yields the final product olaflur in technical purity, in which Nxe2x80x2-octadecyl-Nxe2x80x2,N,N-tris(2-hydroxyethyl)-1,3-propanediamine dihydrofluoride occurs as the main component. The purification of the by-products is dispensed with for cost reasons.
The presence of these by-products was until now not considered to be inconvenient, since in relation to the film formation on the enamel they are of secondary importance. However, it has to be taken into account that in the course of the global tightening of the official approval procedures for pharmaceutical active compounds in future the marketing authorizations for contaminated active compounds will be more difficult to obtain.
The present invention is based on the object of providing active compounds which have an activity comparable with olaflur, but contain less by-products and are simpler to prepare.
The object set is achieved according to the invention by amine hydrofluorides of the general formula (I):
Rxe2x80x94N(CH2CH2OH)2.HF xe2x80x83xe2x80x83(I) 
where R is a straight-chain hydrocarbon residue having 10 to 20 carbon atoms.
It has namely been found that these amine hydrofluorides and mixtures of two or more thereof have an antibacterial activity which is very similar to that of the Nxe2x80x2-octadecyl-Nxe2x80x2,N,N-tris(2-hydroxyethyl)-1,3-propanediamine dihydrofluoride from the already-known olaflur. The antibacterial action manifests itself in the inhibition of the growth of a multiplicity of micro-organisms, for instance of Aspergillus niger, Candida albicans, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus faecalis and Enterobacter cloacae. The amine hydrofluorides according to the invention in particular inhibit the sugar degradation in acid-producing plaque bacteria and, owing to the formation of a hydrophobic film, increase the acid resistance of the hard tooth substance and thus have caries-prophylactic action. They also favour the remineralization of initial carious lesions.
The amine hydrofluorides according to the invention contain straight-chain (i.e. unbranched) hydrocarbon residues. They can have hydrocarbon residues with both an even- and odd-numbered chain length. Residues having an even-numbered chain length are preferred with regard to physiological acceptability. The residues can preferably be fully saturated or mono-, di- or polyunsaturated. Examples of saturated hydrocarbon residues having an even-numbered chain length are decyl, dodecyl (lauryl), tetradecyl (myristyl), hexadecyl (cetyl, palmityl), octadecyl (stearyl) and eicosanyl. Examples of unsaturated residues having an even-numbered chain length are 9-cis-octadecenyl (oleyl), 9-trans-octadecenyl (elaidyl), cis,cis-9,12-octadecadienyl (linolyl), cis,cis,cis-9,12,15-octadecatrienyl (linolenyl) or 9-cis-eicosaenyl (gadolyl). Lauryl, myristyl, cetyl, oleyl and stearyl residues are preferred.
The amine hydrofluorides are prepared according to the invention by reacting an amine of the general formula (II):
Rxe2x80x94N(CH2CH2OH)2 xe2x80x83xe2x80x83(II) 
in which R is a hydrocarbon residue having 10 to 20 carbon atoms, with hydrogen fluoride. The reaction can be carried out in all solvents which have an adequate solubility for the free amine of the formula (II) and are not attacked by hydrogen fluoride. Examples of suitable solvents are C1- to C4-alcohols and dimethyl sulfoxide: ethanol is particularly preferred. The addition of the hydrogen fluoride as an aqueous solution, i.e. as hydrofluoric acid , is preferred. The hydrogen fluoride is preferably added in an amount from 1 to 5, particularly preferably from 1.0 to 1.1, equivalents, based on the amine. The temperature of the reaction is not critical and can in general be between xe2x88x9210 and +100xc2x0 C., whereby the upper limit may be given by the boiling point of the solvent, or the lower limit by the melting point of the solvent. The preferred temperature of the reaction is between 25xc2x0 C. and 40xc2x0 C. After the completion of the addition of the hydrogen fluoride, the reaction mixture can be evaporated and dried, by means of which the amine hydrofluoride according to the invention is obtained. A possible small hydrogen fluoride loss during the evaporation and drying can be compensated by subsequent addition of a corresponding amount of hydrofluoric acid in the preparation of the formulations according to the invention.
The amine of the formula (II) can be prepared in a manner which is known or known per se by hydroxyethylation of a primary amine Rxe2x80x94NH2, in which R has the above meaning, with ethylene oxide (oxirane), the ethoxylation taking place virtually quantitatively only on the nitrogen atom.
The primary amine Rxe2x80x94NH2 can be obtained in a known manner from a fatty acid of the formula Rxe2x80x94COOH, in which R has the above meaning, by means of the synthesis steps amide formation/dehydration/catalytic reduction, as are also used in the synthesis of the already-known olaflur. Suitable fatty acids or fatty acid mixtures of the formula Rxe2x80x94COOH and suitable amines or amine mixtures of the formula Rxe2x80x94NH2 are known and in some cases obtainable commercially.
According to a further variant, the amine of the formula (II) can be prepared by alkylation of diethanolamine in a nucleophilic SN2 substitution:
Rxe2x80x94X+HN(CH2CH2OH)2xe2x86x92Rxe2x80x94N(CH2CH2OH)2.HX 
where Rxe2x80x94X is the alkylating agent, R has the same meaning as in formula (II) and X is, for example, chlorine, bromine or iodine.
The amine of the formula (II) is first obtained here as an ammonium salt. This ammonium salt is deprotonated using a base, for example aqueous NaOH, and then reacted according to the invention with hydrogen fluoride.
The alkylating agent Rxe2x80x94X can be obtained from a corresponding, commercially obtainable fatty alcohol by introducing a leaving group:
Rxe2x80x94OH+HXxe2x86x92Rxe2x80x94X+H2O 
where Rxe2x80x94OH is the fatty alcohol, and HX is, for example, hydrogen chloride, hydrogen bromide or hydrogen iodide.
A separation of possible homologues and/or double bond isomers can be carried out at the stage of the fatty alcohol, e.g. by fractional distillation and/or recrystallisation, so that a pure fatty alcohol is obtained (for the necessary physical data cf., for example, Rxc3x6mpp, Chemielexikon [Chemical Encyclopedia], 9th Edition, Vol. 2, page 1337).
The amine hydrofluorides according to the invention are preferably essentially free of di- or polyamine hydrofluorides, such as are typical of the already-known olaflur. They are free, in particular if the preparation route via the alkylation of highly pure diethanolamine is selected, of products in which the amino groups are over- or under-hydroxyethylated (i.e. in that the amines are quaternary or secondary after the hydroxyethylation) or the hydroxyethyl groups are etherified. The amine hydrofluorides according to the invention have a degree of hydroxyethylation of exactly two, if the route via the alkylation of diethanolamine is selected.
According to the invention, the object is also achieved by an amine hydrofluoride mixture comprising two or more compounds of the formula (I).
The mixtures of amine hydrofluorides according to the invention can be mixtures in any desired ratio of two or more amine hydrofluorides which can be prepared according to one of the above processes.
Mixtures of amine hydrofluorides are preferred which have been obtained from a fatty acid mixture of an animal or vegetable fat or oil and whose hydrocarbon residues R therefore have a frequency distribution dependent on the chain length which reflects the frequency distribution of the corresponding fatty acid homologues in this fatty acid mixture. Such mixtures can be obtained by hydrofluoridation of mixtures of amines of the formula (II). The mixtures of amines are prepared here, starting from an animal or vegetable fat or oil, using the synthesis steps hydrolysis/amide formation/dehydration/catalytic reduction/hydroxy-ethylation in analogy to the corresponding synthesis steps for the already-known olaflur.
Examples of the vegetable oils or fats suitable for these mixtures of amines of the formula (II) are almond oil, avocado pear oil, maize germ oil, cottonseed oil, rapeseed oil, linseed oil, olive oil, peanut oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, soya oil, sunflower oil, wheatgerm oil, babassu oil, coconut oil, palm kernel oil, rape oil and palm oil. Examples of animal fats or oils are bovine tallow, chicken fat, goat""s fat, pork dripping, sheep tallow, various fish oils and whale oil. A preferred animal fat is bovine tallow: preferred vegetable oils are soya oil, rape oil or soya oil/rape oil mixtures. A detailed table with the compositions of the fatty acid mixtures resulting from these animal or vegetable fats or oils is found, for example, in Ullmann""s Encyclopaedia of Industrial Chemistry 5th Edition, Vol. A10, page 176 et seq. The amounts of saturated fatty acids can be increased, if desired, by catalytic hydrogenation.
Mixtures of amines of the formula (II) which have been obtained from a vegetable or animal fat or oil are obtainable commercially. Examples are the products Ethomeen S/12 (obtained from the fatty acid mixture from soya oil), Ethomeen T/12 and Ethomeen HT/12 (both obtained from the fatty acid mixture from bovine tallow, the latter being hydrogenated) marketed by AKZO NOBEL. The main component in S/12 and T/12 is N-oleyldiethanolamine. The applicant was also able to order a mixture of amines of the formula (II) , whose main component is N-stearyldiethanolamine, from WITCO. This mixture is obtained from the fatty acid mixture of bovine tallow, the oleyl residues being hydrogenated to give stearyl residues.
A mixture of amine hydrofluorides according to the invention can also be obtained if a mixture of amine hydrofluorides which has been obtained from the fatty acid mixture of a vegetable or animal fat or oil is mixed with one or more pure amine hydrofluorides. Two or more mixtures of amine hydrofluorides which have been obtained from different fats or oils in each case can also be mixed.
A fat such as is known in the art can also be reduced to a mixture of fatty alcohols, and this fatty alcohol mixture can be processed, as described above for the synthesis of amine hydrofluorides in pure form from pure fatty alcohols, to give a corresponding mixture of amine hydrofluorides.
The invention likewise relates to oral hygiene compositions comprising at least one of the amine hydrofluorides according to the invention in an efficacious amount. They can be prepared in analogy to the conventional oral hygiene compositions and using the customary auxiliaries and additives.
Preferably, the oral hygiene compositions according to the invention can also contain a mixture of amine hydrofluorides obtained from a vegetable or animal oil or fat, in particular from bovine tallow, soya oil, rape oil or soya oil/rape oil mixtures.
In addition to an amine hydrofluoride or a mixture of amine hydrofluorides, oral hygiene compositions according to the invention can also preferably contain tin(II) fluoride. These tin fluoride-containing oral hygiene compositions are active against gingivitis, parodontitis and stomatitis, likewise being caries-prophylactically active due to the content of amine hydrofluorides. In such oral hygiene compositions, the amine hydrofluoride(s) according to the invention bring about a pharmaceutical stabilization of the Sn(II) against precipitation to give insoluble tin(IV) oxide.
The lower limit for the content by weight of the amine hydrofluoride(s) in the oral hygiene composition is determined by the still-significant prophylactic action, i.e. in particular the antimicrobial or caries-prophylactic action. The upper limit for the weight of the amine hydrofluoride(s) is not critical, it should, however, not be too high with respect to possible toxic side effects.
In the case of an oral hygiene composition in the form of toothpastes, it is possible for amine hydrofluorides according to the invention preferably to be contained in amounts from 0.02 to 5% by weight, particularly preferably from 2 to 3% by weight.
The additives and auxiliaries for toothpastes according to the invention are scouring agents, binding agents, plasticizers, moisturizing agents and also flavourings and aromatic substances. Examples of scouring agents are alkaline earth metal phosphates (e.g. dicalcium phosphate dihydrate, dicalcium phosphate anhydride, tricalcium phosphate), insoluble alkali metal metaphosphates, finely ground or colloidal silicas, aluminium hydroxide hydrates, aluminium silicates, aluminium magnesium silicates and alkaline earth metal carbonates. Suitable plastics, e.g. polyethylene, can also be employed. These scouring agents are customarily employed in amounts of 20 to 60% by weight. Binding agents are gelling agents of natural or synthetic origin. Examples of these are water-insoluble alginates, carraghenates, guar gum, tragacanth, water-soluble cellulose ethers (e.g. methylcellulose, hydroxyalkylcelluloses, carboxymethylcellulose), water-soluble salts of polyacrylic acids (Carbopols), aerosils and bentonites. In general, the content of the binding agents is 0.5 to 10% by weight. Examples of plasticizers and moisturizing agents are polyhydric alcohols such as glycerol, propylene glycol, sorbitol, mannitol, glucose syrup, polyethylene glycols, polypropylene glycols and polyvinylpyrrolidone. They are customarily employed in amounts from 10 to 40% by weight. Examples of flavourings are saccharin, quaternary ammonium saccharinates, cyclamates, coumarin and vanillin. Aromatic substances are customarily ethereal oils, e.g. peppermint oil, spearmint oil, aniseed oil, menthol, anethole, citrus oil etc. or other essences such as apple, eucalyptus or spearmint essence.
Rinsing solutions according to the invention are preferably aqueous, alcoholic or mixed aqueous/alcoholic solutions with one or more of the amine hydrofluorides according to the invention. It is possible for the amine hydrofluoride(s) according to the invention to be present in amounts from 0.02 to 2% by weight, preferably 0.2 to 0.3% by weight. Additives and auxiliaries for rinsing solutions, are, for example, the abovementioned flavourings and aromatic substances, but also emulsifiers, wetting agents, sorbitol, xylitol and various drug extracts.
As the carrier material, dental gels according to the invention contain a swollen mixture of natural or synthetic hydrocolloids. Examples of these are methylcellulose, hydroxyalkylcelluloses, carboxymethylcellulose, water-soluble and swellable salts of the polyacrylic acids, alginates, carraghenates and guar gum. The abovementioned flavourings and aromatic substances and moisturizing agents and possibly also pigments can also be admixed in small amounts into the respective gel base. It is possible for one or more of the amine hydrofluorides according to the invention to be contained in amounts from 0.02 to 10% by weight, preferably 4.9 to 5.0% by weight. To conceal the taste and/or as an additional fluoride source, it is also possible to add sodium fluoride, in amounts up to 5% by weight.
Further examples of oral hygiene compositions according to the invention are topical application solutions and chewable tablets. The content of amine hydrofluorides in topical application solutions can alternatively be higher than in rinsing solutions. In topical application solutions it can typically be 5 to 25% by weight, preferably 15 to 25% by weight. The same substances can be used as additives in topical application solutions as in the rinsing solutions. In the case of chewable tablets, amine hydrofluoride contents of typically 0.3 to 12% by weight, preferably 2 to 7% by weight, can be present. Additives for chewable tablets are binding agents and sucrose, glucose, lactose or preferably the non-cariogenic sugar types such as xylitol, mannitol or sorbitol. They can be improved in flavour by addition of aromatic substances. For the production of chewable tablets according to the invention, processes and tabletting presses known from the conventional production of chewable tablets can be employed.
In all oral hygiene compositions according to the invention, tin(II) fluoride can also be added in amounts of, as a rule, 0.001 to 2% by weight, as a solid or as, for example, an aqueous solution. The same additives and auxiliaries can be employed as in the tin fluoride-free oral hygiene compositions. As solutions of tin(II) fluoride are stabilized by addition of the amine hydrofluorides according to the invention, such solutions remain clear over a longer period and no cloudiness occurs. Combinations of the amine hydrofluorides according to the invention and tin(II) fluoride are therefore particularly suitable for use in oral hygiene compositions in the form of rinsing solutions. Rinsing solutions which contain efficacious amounts of one or more amine hydrofluorides and tin(II) fluoride are a preferred embodiment of the oral hygiene compositions according to the invention.
The present invention is now illustrated further by the following examples. All quantitative data in per cent, ppm and parts relate, if not mentioned otherwise, to weights.